Abstract Cardiac transplantation has become a life-saving strategy for patients with irreversible heart disease. While the development of immunomodulatory drugs (IMD) has played a pivotal role in the success of heart transplantation, nonetheless, there is a substantial unmet need to improve the long-term outcomes of heart transplantation. A large number of cardiac transplant recipients lose their heart transplants due to chronic microvascular injuries. Furthermore, they are also at substantial risk for losing their native organs (such as the kidneys) due to the microvascular toxicities. IMD contribute both directly to these microvascular toxicities by mediating endothelial injuries, and indirectly by playing a pathogenic role in the development of diabetes, the metabolic syndrome and hypertension post-cardiac transplantation. Other serious side effects of IMD include systemic infection and post-transplant malignancy. Therefore, there is a significant unmet need for the development of novel strategies which increase the efficacy and reduce the toxicity of IMD. This proposal seeks to establish an innovative nanodelivery system of IMD in heart transplantation. Pursuing our preliminary data, we will test the hypothesis that targeted delivery of IMD to the draining lymph nodes (DLN) and heart allografts increases the efficacy of IMD, thereby significantly reducing their systemic dosing. The latter should result in reduced systemic toxicity as well. The scientific premise of this proposal is soundly supported by the wealth of information demonstrating that lymphoid tissue are the critical loci for the formation of alloreactive T cells, which eventually home to cardiac allografts and cause cardiac rejection. The field of nanotechnology has created unprecedented opportunities to lay the groundwork for transformative approaches to change the landscape of drug delivery. However, the application of nanomedicine to heart transplantation remains to be developed. Over the past several years, we have developed the first class of nanocarriers for the delivery of IMD to DLN and heart transplants with significant clinical efficacy. These data significantly support the feasibility of the proposed studies. In Aim 1, we plan to characterize and further improve the delivery of IMD to the DLN to further promote heart allograft survival. The proposed studies will employ murine heart transplant models, established functional assays and sophisticated imaging studies to better understand the biodistribution of IMD and their nanocarriers. In Aim 2, we will study the underlying mechanisms by which delivering IMD to the DLN controls the balance of alloreactive T cells and regulatory T cells. In Aim 3, we will capitalize on the unique setting of transplantation where we can deliver IMD directly to heart organs prior to transplantation. These innovative and clinically feasible approaches enable for the first-time better control of the organ?s inflammatory milieu which significantly perpetuate chronic rejection. We believe these studies have the potential to yield paradigm-shifting results enabling the development of transformative and innovative approaches to improve heart transplantation outcomes. !